How Nicotine Wrecks Sperm: Antioxidants May Quiet a Cellular Stress Switch in the Testis

Cigarette smoking has long been associated with declining male fertility, but the precise molecular chain of events linking nicotine to damaged sperm has remained frustratingly incomplete. A new study in Reproductive Sciences now maps that chain in detail, showing that nicotine drives testicular injury through a maladaptive endoplasmic reticulum stress response, and that two well-known antioxidant supplements, melatonin and coenzyme Q10, can partially disarm the process. The work, led by Aysel Eraslan Sakar of Hatay Mustafa Kemal University in Turkey, offers one of the clearest experimental demonstrations so far that oxidative stress and ER stress signaling act together to sabotage sperm quality, and that this axis can be pharmacologically targeted.

The endoplasmic reticulum is the cellular factory where newly made proteins are folded, modified, and quality-checked before they move on to their final destinations. Because protein folding is chemically demanding and exquisitely sensitive to the cellular environment, the ER is among the first organelles to falter when a cell is under oxidative assault. When misfolded proteins accumulate, the ER activates a rescue program known as the unfolded protein response, orchestrated by sensor proteins including PERK, IRE1α, and ATF6, together with the chaperone GRP78. If the stress is mild, this response restores balance. If it is prolonged or severe, the response turns lethal, ramping up the transcription factor ATF4 and its downstream partner CHOP, a protein that pushes stressed cells toward apoptosis.

Nicotine, the addictive alkaloid in tobacco, is a potent pro-oxidant that generates reactive oxygen species and depletes cellular antioxidant defenses. Earlier studies had implicated nicotine in testicular damage, showing reduced gametogenesis, altered steroidogenesis, and increased apoptosis in animal models, and had even linked nicotine exposure to ER stress in tissues such as the placenta and airway smooth muscle. What remained unclear was whether the ER stress pathway was a genuine mechanistic driver of nicotine-induced sperm dysfunction in the testis, and whether antioxidants could intervene at that specific signaling node rather than merely mopping up free radicals.

To answer these questions, the researchers worked with 48 two-month-old male Wistar albino rats, dividing them into six experimental groups: an untreated control, a nicotine-exposed group, three groups receiving nicotine together with melatonin, coenzyme Q10, or both compounds, and a group receiving the two antioxidants without nicotine. The design allowed the team to disentangle the toxic effects of nicotine from the protective effects of each supplement, and to test whether the combination offered any advantage over either compound alone. Sperm quality was assessed using standard andrological measures, while testicular tissue was examined for oxidative stress markers, ER stress gene expression, histopathology, and the immunohistochemical localization of key stress proteins.

The results were striking. Nicotine exposure significantly impaired sperm motility and membrane integrity while increasing abnormal sperm morphology, sperm mortality, and apoptosis, with all of these changes reaching high statistical significance. Biochemically, the nicotine-exposed testes showed elevated lipid peroxidation, a hallmark of oxidative damage to cellular membranes, alongside a collapse of antioxidant defenses, including reduced levels of glutathione, glutathione peroxidase, and catalase. In other words, nicotine created a double hit: it flooded the tissue with reactive oxygen species while simultaneously stripping away the enzymes and molecules that would normally neutralize them.

The critical new finding concerned the ER. In the nicotine group, the expression of a battery of ER stress-associated genes was markedly upregulated, including ATF4, ATF6, CHOP, GRP78, IRE1α, and PERK, the full cast of the canonical unfolded protein response. Immunohistochemistry confirmed increased CHOP immunoreactivity in the tissue, indicating that the pro-apoptotic arm of the ER stress response was not merely transcribed but translated into accumulated protein. This pattern suggests that nicotine pushes testicular cells past the adaptive phase of ER stress and into the maladaptive, death-signaling phase, providing a mechanistic bridge between oxidative damage and the observed sperm apoptosis.

Antioxidant treatment changed the picture substantially. Melatonin, the pineal hormone best known for regulating circadian rhythm but also a versatile direct and indirect antioxidant, and coenzyme Q10, an essential component of the mitochondrial electron transport chain and a lipid-soluble radical scavenger, each partially restored sperm quality and antioxidant capacity when given alongside nicotine. At the molecular level, the supplements significantly downregulated the ER stress gene panel, tamping down the expression of ATF4, ATF6, CHOP, GRP78, IRE1α, and PERK, and reducing CHOP immunoreactivity in the tissue. Histopathological analysis showed corresponding protection of testicular architecture, preserving the seminiferous environment in which sperm develop.

One detail of the data may prove particularly interesting to researchers. Coenzyme Q10 selectively enhanced XBP-1 immunoreactivity, a marker associated with the IRE1α branch of the unfolded protein response. Because the IRE1α–XBP-1 arm is generally considered adaptive, promoting protein folding capacity and cellular survival rather than death, this selective effect hints that coenzyme Q10 may not simply suppress ER stress wholesale but may help re-balance the response toward its protective branch. Melatonin, meanwhile, has previously been shown to modulate ER stress in contexts ranging from arsenite-induced neurotoxicity to fulminant hepatitis and testicular injury from bisphenol A and phthalates, and the new findings extend that mechanistic portfolio to nicotine-driven reproductive damage.

The authors are careful about scope. This is a rat study, with controlled dosing and a defined exposure window, and the leap from rodent testes to human male fertility is neither automatic nor trivial. The supplements produced partial rather than complete protection, which itself is informative: nicotine inflicts damage through multiple converging pathways, including vascular effects, hormonal disruption, and direct genotoxicity, so no single antioxidant can be expected to erase the harm. Data from the study are available upon reasonable request, and the work was supported by the Scientific Research Projects Coordination Unit of Hatay Mustafa Kemal University, with ethics approval from the institution’s Local Animal Ethics Committee.

Even with those caveats, the study carries real weight for a public health conversation that often treats smoking-related fertility damage as an afterthought. It identifies a specific, druggable signaling axis, the oxidative stress–ER stress–CHOP cascade, as a mediator of nicotine’s assault on sperm, and it demonstrates that two inexpensive, widely available compounds can intervene at that axis in a living animal. For the millions of smokers whose fertility may be quietly eroding, the message is not that a supplement can undo the damage of smoking, but that the biology of that damage is now understood well enough to be targeted, and that the surest intervention remains removing the toxin itself. Translational studies in human populations will be needed before melatonin or coenzyme Q10 can be recommended clinically, but as a proof of mechanism, this work sharpens the picture of how tobacco smoke reaches deep into the cellular machinery of reproduction.

Subject of Research: Nicotine-induced oxidative stress and endoplasmic reticulum stress signaling in rat testis and its attenuation by melatonin and coenzyme Q10

Article Title: Targeting the Nicotine-driven Maladaptive ER Stress Axis: Protective Roles of Melatonin and Coenzyme Q10 in Rat Testis

Article References: Eraslan Sakar, A., Yildiz, C., Coskun, N., Sengul, S. A., Akcakavak, F. K., Kutlu, T., Sayan, M., & Karabulut, D. (2026). Targeting the Nicotine-driven Maladaptive ER Stress Axis: Protective Roles of Melatonin and Coenzyme Q10 in Rat Testis. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02235-z

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02235-z

Keywords: nicotine, endoplasmic reticulum stress, melatonin, coenzyme Q10, sperm quality, male fertility, oxidative stress, testis, apoptosis, unfolded protein response, CHOP, rat model